Cyclic aryl hydroxamic acids, derivatives thereof and method of use as anti-allergy agents

ABSTRACT

Cyclic aryl hydroxamic acids and derivatives thereof are provided having the structure    &lt;IMAGE&gt;  I  wherein R is H or arylalkyl, and including acid-addition salts thereof. These compounds are useful as inhibitors of leukotriene production and as such are useful as antiallergy, anti-inflammatory and anti-psoriatic agents.

DESCRIPTION OF THE INVENTION

The present invention relates to cyclic aryl hydroxamic acids andderivatives thereof which prevent leukotriene formation in macrophagesand as such are useful, for example, as antiallergy agents,anti-inflammatory agents and in the treatment of psoriasis. Thesecompounds have the structural formula ##STR2## wherein R is H orarylalkyl and including pharmaceutically acceptable salts thereof.

As to the pharmaceutically acceptable salts, those coming within thepurview of this invention include the pharmaceutically acceptableacid-addition salts. Acids useful for preparing these acid-additionsalts include, inter alia, inorganic acids, such as the hydrohalicacids, (e.g., hydrochloric and hydrobromic acid), sulfuric acid, nitricacid and phosphoric acid, and organic acids such as maleic, fumaric,tartaric, citric, acetic, benzoic, 2-acetoxybenzoic, salicylic; succinicacid, theophylline, 8-chlorotheophylline, p-aminobenzoic,p-acetamidobenzoic or methanesulfonic.

In addition, a method is provided for treating asthma mediated byleukotrienes in a mammalian species in need of such treatment, whichmethod includes the step of administering to a mammalian host aneffective amount of a compound of formula I or a pharmaceuticallyacceptable salt thereof.

Thus, compounds of formula I of the invention include compounds of thefollowing structures: ##STR3##

The term "arylalkyl" as employed herein has the structure aryl-(CH₂)_(x)-- wherein x is an integer from 1 to 10 and preferably from 2 to 6 andmay include 1 or 2 lower alkyl substituents, such as ##STR4##

The term "lower alkyl" or "alkyl" as used herein refers to straight andbranched chain radicals of up to 12 carbons and preferably 1 to 8carbons, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl,isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl,2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, the variousbranched chain isomers thereof.

The term "aryl" or "Ar" as employed herein as part of the arylalkylgroup refers to monocyclic or bicyclic aromatic groups containing from 6to 10 carbons in the ring portion, such as phenyl, naphthyl, substitutedphenyl or substituted naphthyl wherein the substituent on either thephenyl or naphthyl may be 1 or 2 lower alkyl groups, 1 or 2 lower alkoxygroups and/or 1 or 2 hydroxy groups.

Thus, the term "aralkyl", "arylalkyl" or "aryl-lower alkyl" as usedherein includes, for example, phenylethyl, phenylpropyl, phenylbutyl,phenylpentyl and the like.

Compounds of formula I are prepared by treating a cooled solution of anamide of the structure IV ##STR5## (wherein Prot. represents aprotecting group such as tetrahydropyranyl) in an organic solvent suchas tetrahydrofuran, ethyl ether or benzene with a solution ofbutyllithium (preferably n-butyllithium) in hexane, warming the reactionto room temperature, cooling to from about -100° to about -78° C.,treating the reaction mixture with ethylene oxide solution intetrahydrofuran and then boron trifluoride etherate and maintaining thereaction mixture at a temperature of from about -100° to -78° C. to formalcohol V ##STR6## and treating V in benzene with sodium hydride orother base, such as potassium hydride or potassiumbis(trimethylsilyl)amide in the presence of tosyl chloride to form thecompound VI ##STR7## Compound VI is treated with an acid such aspyridinium p-toluene sulfonic acid or hydrochloric acid in aqueousmethanol or ethanol or other alcohol under mild heating (from about 40to about 65° C.) to form compound I.

Starting compound IV wherein R is H, that is ##STR8## may be prepared,for example, where Prot. represents tetrahydropyranyl, by treatingO-tetrahydropyran-2-yl hydroxylamine (prepared as described in Example2, Part A of U.S. Pat. No. 4,607,053) with benzoyl chloride in thepresence of weak organic base such as triethylamine or pyridine, andmethylene chloride or other solvent, such as ethyl ether or benzene.

Starting compound IV wherein R is arylakyl, that is IVB ##STR9## may beprepared by treating a bromo compound of the structure VII

    aryl--(CH.sub.2).sub.x-1 Br                                VII

with triphenylphosphine to form compound VIII

    aryl--(CH.sub.2).sub.x-1 --P(C.sub.6 H.sub.5).sub.3 Br     VIII

which is dissolved in a solvent such as tetrahydrofuran, ethyl ether orbenzene, cooled to -20° to 0° C., and treated under inert atmosphere(such as argon), with potassium-t-amylate and methyl 4-formylbenzoate,A, that is ##STR10## in th organic solvent described above, (that is,tetrahydrofuran, ethyl ether or benzene) to form IX ##STR11## CompoundIX is then hydrogenated by treatment with hydrogen in the presence of apalladium on carbon catalyst to form X ##STR12## Compound X is thenhydrolzed to the corresponding acid XI by treating X with strong basesuch as alkali metal hydroxide (for example, NaOH or LiOH) in thepresence of aqueous methanol and organic solvent, such astetrahydrofuran, to form acid XI ##STR13## which is then protected, forexample, by reacting with O-tetrahydropyran-2-yl hydroxylamine in thepresence of dicyclohexnyl carbodiimide and hydroxy benzotriazolemonohydrate to form VB (wherein the protecting group istetrahydropyranyl).

The compounds of the invention are inhibitors and prevent leukotrieneformation in macrophages (Samuelsson, B., Science, vol. 220p. 568-575,1983). The administration of compounds of this invention to humans oranimals provides a method for treating allergy of a reagin or non-reaginnature. Asthma is preferably treated but any allergy whereinleukotrienes are thought to be involved as pharmacological mediators ofanaphylaxis can be treated. For example, the compounds of this inventioncan be used for treatment of such conditions as allergic rhinitis, foodallergy and utricaria as well as asthma.

An effective but essentially non-toxic quantity of the compound isemployed in treatment.

The compounds of the invention can be administered orally orparenterally to various mammalian species known to be subject to suchmaladies. e.g., humans, cats, dogs, and the like in an effective amountwithin the dosage range of about 1 to 100 mg/kg, preferably about 1 to50 mg/kg and especially about 2 to 25 mg/kg on a regimen in single or 2to 4 divided daily doses.

The active substance can be utilized in a composition such as tablet,capsule, solution or suspension containing about 5 to about 500 mg perunit of dosage of a compound or mixture of compounds of formula I. Theymay be compounded in conventional matter with a physiologicallyacceptable vehicle or carrier, excipient, binder, preservative,stabilizer, flavor, etc. as called for by accepted pharmaceuticalpractice. Also as indicated in the discussion above, certain membersadditionally serve as intermediates for other members of the group.

The following Examples represent preferred embodiments of the invention.Unless otherwise indicated, all temperatures are expressed in °C. TLCplates were visualized by spraying and heating with 5% phosphomolybdicacid in ethanol.

EXAMPLE 1 3,4-Dihydro-2-hydroxy-6-(4-phenylbutyl)-1(2H)-isoquinolinoneA. N-(Tetrahydropyran-2-yloxy)-4-(4-phenylbutyl))benzamide

(1) 3-Phenylpropyl triphenylphosphonium bromide

A magnetically stirred suspension of 1bromo-3-phenylpropane (Aldrich,13.7 ml, 90 mmol) and triphenylphosphine (47.2 g, 180 mmole) was heatedat 100° C. (Oil bath) for 2.0 hours. The resulting while solid was thencooled and triturated with ether (5X) to remove most of the unreactedtriphenylphosphine, to give Part A(1) compound in 96% yield (wt. 40.0g).

(2) 4-(Phenyl-1-butenyl)benzoic acid, methyl ester

To a 0° solution of Part A (1) compound (3.55 g, 1.25 eq) in 30 ml ofdry THF under Argon was added K-t-amylate (3.9 ml, 1.1 eq). Afterstirring for 30 minutes at 0° C. then allowing to warm to roomtemperature, a solution of methyl 4-formylbenzoate (1.0 g, 6.1 mmol,Fluka) in ˜8 ml of dry THF was added dropwise. This solution was stirredfor 3 hours at room temperature, then diluted with ˜1 ml of H₂ O, andconcentrated to remove most of the THF. EtOAc (18 200 ml) was added andthe mixture was washed with H₂ O, 1N HCl (2X) and brine. After dryingover anhydrous MgSO₄ the solvent was removed in vacuo to yield a yellowoil which solidified. Column purification of this crude product onsilica gel eluted with 95:5 hexane/EtOAc yielded after concentrationtitle aldehyde 1.5 g (93%) as a clear oil.

(3) 4-(4-Phenylbutyl)benzoic acid, methyl ester

To a stirring solution of Part A(2) ester (850 mg, 3.2 mmol) in 20 ml ofCH₃ OH was added Pd/c (5%) 85 mg under Argon. Hydrogen gas was added andthe reaction was allowed to stir under H₂ (balloon) for 1 hour. Themixture was filtered (millipore) and concentrated in vacuo to give titleester as a clear oil, 850 mg (˜100%).

(4) 4-(4-Phenylbutyl)benzoic acid

A solution of Part A(3) compound (850 mg; 3.2 mmol), 2N NaOH (4.8 ml,3.0 eq) in 35 ml of CH₃ OH/THF (5:1) was heated to reflux for 21/2hours. The solution was acidified with 1N HCl (15 ml). THF was removedin vacuo and a white solid was collected by filtration. This solid wasdissolved in ETOAc and washed with 1/2 saturated brine, then brine.After drying over anhydrous MgSO₄, concentration gave title acid 680 mgas a white solid. The filtrate, from the original filtration, wasextracted with ETOAc 2X (75 ml portions) washed with 1/2 saturatedbrine, then brine. Concentration after drying over anhydrous MgSO₄ gave80 mg of title acid, a total yield of 91%.

(5) N-(Tetrahydropyran-2-yloxy)4-(4-phenylbutyl)benzamide

To a 0° C. solution of Part A(4) acid (700 mg, 2.8 mmol) in 40 ml of CH₂Cl₂ under Argon was added O-tetrahydropyran-2-ylhydroxylamine (preparedas described in U.S. Pat. No. 4,607,053, Example 2Part A) (654 mg, 2.0eq.), hydroxybenzotriazole hydrate (460 mg, 1.2 eq.), dicyclohexylcarbodiimide (700 mg, 1.2 eq.) sequentially. After 0.5 hour at 0° thesolution was allowed to warm to room temperature and stir under Argonfor 4 hours. The solution was filtered, concentrated in vacuo to yield awhite solid which was chromatographed on LPS-1 silica gel eluting with6:4 hexane/EtOAc. Product containing fractions were evaporated to givetitle compound as an oil, 1.0 g (˜100%).

B. N-(Tetrahydropyran-2-yloxy)4-(4-phenylbutyl)2-hydroxyethylbenzamide

To a solution of 975 mg (2.76 mmol) of Part A(5) compound in 15ml of dryTHF cooled in an ice-bath was added dropwise 2.5 ml (2.4M in hexane, 6.0mmol, Alfa) of n-butyllithium solution. The reaction mixture was warmedto room temperature, stirred 15 minutes then cooled to -78°. To theresulting yellow-brown solution was added 1.5 ml (2.0M in THF, 3.0 mmol)of ethylene oxide solution followed by dropwise addition of 0.37 ml (3.0mmol) of boron trifluoride etherate. The reaction mixture was stirredfor 15 minutes at -78°, quenched with 1 ml of methanol, added to 60 mlof H₂ O and extracted with three 20 ml portions of ethyl acetate. Theorganic extracts were combined, dried (MgSO₄) and concentrated in vacuoto give a yellow oil. The crude material was purified by flashchromatography (15×5.0 cm, 2:1 EtOAc/petroleum ether) to afford 348 mg(32%) of title compound as a pale yellow oil.

270 MHz ¹ H NMR (CDCl₃): δ1.66 (m, 11H, PhCH₂ (CH₂)₂ --, --OCH₂ (CH₂)₃-- of THP ring, --OH); 2.63 (m, 4H, benzylic --CH₂ --); 2.97 (t, J=4,1H, --CH₂ CH₂ OH); 3.08 (t, J 5, 1H, --CH₂ CH₂ OH); 3.66 (m, 1H, --OCH₂-- of THP ring); 3.94 (m, 3H, --OCH₂ -- of THP ring, --CH₂ OH); 5.14 (s,1H, THP methine); 7.00-7.45 (m, 8H, aromatic); 9.34 (s, 1H, --NH--).

MS (CI); 398 (M+H).

TLC: R_(f) (Silica gel, 2:1 ETOAc/petroleum ether)=0.23, PMA and UV.

C.3,4-Dihydro-2-(tetrahydropyran-2-yloxy)-6-(4-phenylbutyl)-1-(2H)-isoquinolinone

To a solution of 318 mg (0.80 mmol) of Part B compound in 5 ml of drybenzene was added 78 mg (48% in oil, 1.6 mmol) of sodium hydridedispersion; then after 5 minutes, 153 mg (0.80 mmol) of recrystallizedtosyl chloride was added. The reaction mixture was stirred for 16 hoursthen an additional 50 mg (1.0 mmol) of sodium hydride dispersion and 50mg (0.26 mmol) of tosyl chloride were added. The resulting slurry wasstirred for an additional 4 hours, added to 1 5 ml of H₂ O and extractedwith two 10 ml portions of ethyl acetate. The combined organic extractswere dried (MgSO₄) and concentrated in vacuo to give an oil. The crudeoil was purified by flash chromatography (10×3.0 cm, 1:1:5 EtOAc/CHCl₃/petroleum ether) to afford 190 mg (63%) of title compound as a paleyellow solid, m.p. 62°-64° C.

Partial 60 MHz ¹ H NMR (CDCl₃) δ: 3.38-4.38 (m with T, J=6, at δ 3.92,4H, --OCH₂ -- of THP ring and triplet corresponding to --NCH₂ --); 5.25(m, 1H, THP methine); 6.85-7.45 (m, 7H, aromatic ); 8.07 (d, J=8, 1H,aromatic C8 proton).

MS (CI); 296 (M+H-OTHP)⁺.

TLC: R_(f) (silica gel, 2:2:5 CHCl₃ /EtOAc/petroleum ether)=0.44, PMAand UV.

D. 3,4-Dihydro-2-hydroxy-6-(4-phenylbutyl)-1(2H)-isoquinolinone

A solution of 180 mg (0.47 mmol) of Part C compound, 130 mg (0.52 mmol,Aldrich) of pyridinium p-toluenesulfonic acid and 5 drops of H₂ O in 5ml of methanol was refluxed for 3 hours. The reaction mixture wascooled, concentrated in vacuo and the residue added to 15 ml of ethylacetate. The solution was washed with 15 ml of H₂ O, dried (Na₂ SO₄) andconcentrated in vacuo to give a solid. Recrystallization(EtOAc/petroleum ether) of the solid afforded 90 mg (65%) of titleproduct as a white powder, m.p. 82°-83°.

IR(KBr) 3429, 3062 (broad), 2933, 1648, 1626, 1613, 1570, 1483, 1453,1333, 1247, 964, 698 cm⁻¹.

270 MHZ¹ H NMR(CDCl₃) δ: 1.66 (m, 4H, --(CH₂)₂ CH₂ Ph) 2.64 (m, 4H,--CH₂ (CH₂)₂ CH₂ Ph) 3.14 (dd, J=7, 7, 2H, --NHCH₂ CH₂) 3.88 (dd, J=7, 72H, --NCH₂ --) 6.98 (s, 1H, aromatic C5 proton) 7.10-7.35 (m, 6H,aromatic) 7.95 (d, J=8, 1H, aromatic C8 proton) 8.38 (br s, 1H, --OH).

MS (CI): 296 (M+H)⁺.

TLC: R_(f) (silica gel, 1:9 MeOH/CH₂ Cl₂)=0.61, PMA (faint) and UV.

Microanalysis calcd for C₁₉ H₂₁ NO₂ : C, 77.26; H, 7.17; N, 4.74. Found:C, 76.95; H, 7.08; N, 4.80.

EXAMPLE 2 3,4-Dihydro-2-hydroxy-1(2H)-isoquinolinone A.N-(Tetrahydropyran-2-yloxy)benzamide

To a solution of 1.00 g (8.55 mmol) ofO-tetrahydropyran-2-ylhydroxylamine (prepared as described in U.S. Pat.No. 4,607,053, Example 2, Part A) and 1.4 ml (10 mmol) of sieve-driedtriethylamine in 15 ml of dry CH₂ Cl₂ cooled to -20 was added a solutionof 1.50 g (10.7 mmol) of benzoyl chloride in 5 ml of CH₂ Cl₂ over 10minutes. The reaction mixture was stirred for 1 hour then diluted with15 ml of ethyl acetate. The resulting slurry was filtered and thefiltrate concentrated in vacuo to give a solid. Recrystallization(EtOAc/petroleum ether) of the solid afforded 1.45 g (77%) of titlecompound as white crystals, m.p. 130°-134°.

60 MHz ¹ H NMR (CDCl₃) δ: 1.40-2.10 (m, 6H, --OCH₂ (CH₂)₃ --THP ring);3.40-4.30 (m, 2H, --OCH₂ -- of THP ring); 5.07 (m, 1H, THP methine);7.10-7.90 (m, 5H, aromatic).

TLC: R_(f) (silica gel, 1:1 EtOAc/petroleum ether)=0.42, UV and PMA.

B. N-(Tetrahydropyran-2-yloxy)-2-(hydroxyethyl)benzamide

To a solution of 490 mg (2.22 mmol) of Part A compound in 10 ml of drytetrahydrofuran at 0° was added 2.0 ml (2.4M in hexane, 4.8 mmol), ofn-butyllithium solution. The reaction mixture was warmed to roomtemperature, stirred for 30 minutes then cooled to -78°. To theresulting orange-yellow solution was added 1.8 ml (2M intetrahydrofuran, 3.6 mmol) of an ethylene oxide solution followed by0.45 ml (3.6 mmol, MCB) of boron trifluoride etherate. The reactionmixture was stirred for 15 minutes, quenched by adding to saturatedaqueous NaHCO₃ then added to 40 ml of saturated aqueous NaCl solutionand extracted with four 25 ml portions of ethyl acetate. The organicextracts were combined, dried (Na₂ SO₄) and concentrated in vacuo togive an oil. The crude material was purified by flash chromatography(12×3 cm, 3:1 EtOAc/petroleum ether) to afford 285 mg (49%) of titlecompound as a pale yellow oil.

60 MHz ¹ HNMR(CDCl₃) δ: 1.20-2.15 (m, 6H, --OCH₂ (CH₂)₃ -- of THP ring);2.85 (t, J=6, 2H, benzylic methylene); 3.25-4.70 (m, 6H, --NH--, --CH₂OH, --OCH₂ -- of THP ring); 5.03 (br s, 1H, THP methine); 7.20 (m, 4H,aromatic).

MS(CI): 266 (M+H⁺).

TLC: R_(f) (silica gel, 2:1 EtOAc/petroleum ether)=0.18, PMA and UV.

C. 3,4-Dihydro-2-tetrahydropyran-2-yloxy-1(2H)-isoquinolinone

An oil dispersion of 130 mg (50%, 2.7 mmol, Alfa) of sodium hydride waswashed several times with petroleum ether to remove the oil, then 5 mlof dry benzene was added, followed by a solution of 320 mg (1.21 mmol)of Part B compound in 5 ml of benzene. The reaction mixture was heatedto 50° for 15 minutes, cooled to room temperature, then 275 mg (1.44mmol) of recrystallized tosyl chloride was added. The slurry was stirredfor 14 hours, added to 15 ml of 1M aqueous NaOH solution and extractedwith two 10 ml portions of ethyl acetate. The organic extracts werecombined, dried (MgSO₄) and concentrated in vacuo to afford an oil. Thecrude oil was purified by flash chromatography (12×3.0 cm, 1:4EtOAc/petroleum ether) to afford 174 mg (58%) of title compound as acolorless oil.

60 MHz ¹ H NMR(CDCl₃) δ: 1.25-2.20 (m, 6H, --OCH₂ (CH₂)₃ -- of THPring); 3.20 (dd, J=3, 7, 2H, benzylic --CH₂ --); 3.40-4.30 (m with t,J=6, at δ3.90, 4H, --NCH₂ -- and --OCH₂ -- of THP ring); 5.20 (m, 1H,THP methine); 7.27 (m, 3H, aromatic); 8.07 (dd, J=2, 6, 1H, aromatic).

TLC: R_(f) (silica gel, 2:1 EtOAc/petroleum ether)=0.40, PMA and UV.

D. 3,4-Dihydro-2-hydroxy-1(2H)-isoquinolinone

A solution of 100 mg (0.40 mmol) of Part C compound and 110 mg (0.44mmol) of pyridinium p-toluenesulfonate in 3 ml of methanol containingthree drops of H₂ O was refluxed for 3 hours. The reaction mixture wascooled, concentrated in vacuo and the residue partitioned between 10 mlof H₂ O and 10 ml of ethyl acetate. The organic layer was separated andthe aqueous phase was extracted with two additional 10 ml portions ofethyl acetate. The combined organic extracts were dried (Na₂ SO₄) andconcentrated in vacuo to give an oil. The crude oil was crystallized(EtOAc/petroleum ether) to afford 27 mg (42%) of title product as whitecrystals, m.p. 95°-96°.

IR(KBr) 3434, 3000 (broad), 1654, 1576, 1483, 1441, 1335, 1305, 1243,961, 738, 687 cm⁻¹.

270 MHz¹ H NMR(CDCl₃) δ: 3.20 (t, J=7, 2H, benzylic --CH₂ --); 3.92 (t,J=7, 2H, --CH₂ N--); 7.21 (d, J=7, 1H, aromatic C5 proton); 7.34 (dd,J=8, 8, 1H, aromatic C6 or C7 proton); 7.45 (dd, J=7, 7, aromatic C6 orC7 proton); 8.06 (d, J=6, 1H, aromatic C8 proton).

MS(CI): 164 (M+H)⁺.

TLC: R_(f) (silica gel, 1:19 MeOH/CH₂ Cl₂)=0.31, PMA and UV.

Anal Calcd for C₉ H₉ NO₂ : C, 66.25: H, 5.56; N, 8.58; Found: C, 65.97;H, 5.64; N, 7.98.

EXAMPLES 3 TO 17

Following the procedures as outlined in the Specification and theworking Examples, the following additional compounds in accordance withthe present invention may be prepared.

    ______________________________________                                         ##STR14##                                                                    Ex. No.        R                                                              ______________________________________                                        4.             C.sub.6 H.sub.5 CH.sub.2                                       5.             C.sub.6 H.sub.5 (CH.sub.2).sub.2                               6.             C.sub.6 H.sub.5 (CH.sub.2).sub.3                               7.             C.sub.6 H.sub.5 (CH.sub.2).sub.5                                               ##STR15##                                                                     ##STR16##                                                     10.                                                                                           ##STR17##                                                                     ##STR18##                                                                     ##STR19##                                                                     ##STR20##                                                                     ##STR21##                                                                     ##STR22##                                                                     ##STR23##                                                                     ##STR24##                                                     ______________________________________                                    

What is claimed is:
 1. A compound having the structure ##STR25## whereinR is H or arylalkyl, which has the structure aryl-(CH₂)_(x) --wherein xis 1 to 10 and aryl refers to a monocyclic or bicyclic aromatic grouphaving from 6 to 10 carbons in the aromatic ring which may beunsubstituted or substituted with 1 or 2 lower alkyl groups, 1 or 2lower alkoxy groups and/or 1 or 2 hydoxy groups; and alkyl or loweralkyl by itself or as part of another group refers to straight orbranched chain radicals having 1 to 12 carbons, and includingpharmaceutically acceptable acid-addition salts thereof.
 2. The compoundas defined in claim 1 wherein R is H.
 3. The compound as defined inclaim 1 wherein R is arylalkyl.
 4. The compound as defined in claim 3wherein R is aryl(CH₂)_(X) --wherein x is 2 to
 6. 5. The compound asdefined in claim 1 wherein R is phenylethyl, phenylpropyl orphenylbutyl.
 6. The compound as defined in claim 1 having the name3,4-dihydro-2-hydroxy-6-(4-phenylbutyl)-1(2H)-isoquinolinone.
 7. Thecompound as defined in claim 1 having the same3,4-dihydro-2-hydroxy-1(2H)-isoquinolinone.
 8. A composition forinhibiting allergic conditions mediated by leukotrienes in a mammalianspecies, comprising an effective amount of a compound as defined inclaim 1 or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier thereof.
 9. A method of inhibitingleukotriene biosynthesis to treat inflammation or psoriasis, whichcomprises administering to the circulatory system of a mammalian host aneffective amount of a compound as defined in claim
 1. 10. The method asdefined in claim 9 wherein said compound is administered in an amountwithin the range of from about 1 to about 100 mg/kg.
 11. A method fortreating asthma in a mammalian species in need of such treatment, whichcomprise administering to a mammalian host an effective amount of acompound as defined in claim 1.